Quaternary ammonium compounds



Patented Feb. 10, 1948 UNITED STATES PATENT OFFICE 2635153., QUATERNABY AMMONIUM COMPOUNDS William S. Gump, Montelair. N. 1., assignor to Burton '1. Bush, Inc New York, N. Y., a corporation of New Jersey No Drawing. Application February 29, 1944, Serial No. 624.463

5 Claims. (Cl. 260-5675) 2 This invention relates to new quaternary am- Bl monium compounds and to a process for making R: tha --CH:- and -N R An object of this invention is to provide new An quaternary ammonium compounds possessing de- -'sirable bactericidal properties. A further object is a simple and efllcient process for making such compounds. Other objects will appear to those skilled in the art from the following description.

These objects are accomplished by providing a series of new quaternary ammonium compounds, which may be represented by the following general formula:

radicals in either the ortho, meta, or para, positions. Substitution in the arylene radical may be in any available position and may be eflected, for example, by alkyl or halogen radicals, or both.

The new quaternary ammonium compounds are made by a process which involves treatin an ether having the following general formula:

wherein R1. R2, R4 and Ar have the same significance as above, with a stoichiometrical amount of inorganic or organic acids or alkyl esters of polybasic inorganic acids, at elevated temperatures,

and, if desired, in the presence of inert solvents.

As exemplifying specific ethers which may be employed in this invention, the following may be 25 mentioned:

Name of Ether Chemical Formula Boiling Range, O.

4-N,N-dimethyiaminobenzyl-ndodecyl cameo-030M011 210-212 at 4 mm. Hz.

2-methyl-5-N,N-dimethylaminobenzyl-n-dodecyl C H -O-dJH; 2119-207 at 4 mm. Hg.

Nwflili 4-N.N- iimethylaminobonzyl-n-totndocyl Cflip-O-fiE-O-N-(CHQ; Riv-212 at 4 mm. Hg.

+N.N-diethylamlnobenzyl-n-dodocyl..........................

t methyl+N,N-dimethylaminobenzyl-n-dodwyl-....-........

amem i-emmnmem nmimm haml....-.........

2-metbyl-5-N,N-dimethyiaminobonzyl-Iethyl-n-hexyL......,,

2219-230 at H mm. Hg.

cunl-o-o mono. aur-nrsu-smm. a

CnHg-O-C mom w-zn' in mm. Hz.

I cm-o-c musta 4 mm. H:-

Name oi Ether Chemical Formula Boiling Range, O.

7 (3B, z-methyl-t-Nfi-dimethylmlnobenzyl-n-octyl CuHnr-O-CHu-Q iw-iao' at 6 mm. H

7 N(CH:):

2meihyl-5-N,N'dlmethylamlnobenzyl-n-decyla CuHn-OCH 183-l85' at 5 mm. Hg.-

mom).

fl-methyl-o-N,N-dimethyiaminobenzyi-n-tetmdecyl CuHa-O-CH 289-236 at 6 mm. Hg.

N 1): CH:

@methyl-i-NN-dlcthylaminobenzyl-n-dodeeyl i-chloro-t-NN-dlmotbylamlnobenzyl-n-dodecyl Ichloxo-i-NN-dlmethylamlnobenzyl-n-deeyl 8-chloro-4-N.N-dimethylaminobenzyl-n-dodecyl Hhloro-l-NN-dimethyhmlnobenzyl-n-hexadecyl B-broino-G-NN-dlmethylaminobemyl-n-dodecyl.

Marc-snowman cima-o-cm-O-Nwm), GuHa-W-CHv-O-NWEH K Oa 228-%3 at 4 mm. Hg.

W-m' at 4mm. Hg.

W-m' at 4 mm. Hg.

All of the foregoing e'thers are yellow, viscous oils and may be made by eflecting a, reaction Exmu: 1

Preparation of 4-NJV-dimethulamino benzyl alcohol A-mixture of"336 grams N,N-dimethyl aniline} 450 grams concentrated hydrochloric acid (Sp. G=1.19) and 1350 grams aqueous formaldehyde (39%) were kept at 37 C.-for 48 hours. The

mixture was then cooled in an ice bath and 900 70 grams crushed ice added. A cold (5 C.) solution of 300 grams of sodium hydroxide in 400 grams of water is added in small portions under stirring so that the temperature did not rise Fraction Yield, grams The residue. consisting mainly of 4,4'-tetramethyldiamino diphenylmethane, weighed 28 grams. Fraction HI represented the desired 4-N,N-dimethylamino benzyl alcohol.

Preparation of l-MN-dimethylaminobenzyl-ndodecyl ether 9.2 grams of sodium were cut into small, thin pieces and added to 92 grams of xylene which had been dried over sodium.- The mixture was well stirred and heated to reflux temperature; 88 grams of 4-N.N-dimethylamino benzyl alcohol were then dropped in during one hour. Approxi above 0 C. The oil was then extracted from the 76 mately another hour of refluxing was needed unram -120 44 I 120-210 40 TI 210-212 to Fractions I and II consist of the unchanged alcohol and lauryl chloride. Fraction III represents the desired 4-N,N-dimethylaminobenzyl-ndodecyi ether in a yield of 92% of the theory, taking into account the recovered 4-N.N-dimethylaminohenzyl alcohol and lauryl chloride.

This novel ether, 4-N,N-dimethylaminobenzyln-dodecyl ether, is a yellowish. viscous oil, havlnl a boiling point of 210-212 C. at 4 mm. of mercury pressure.

Preparation of l-trimethylammonium benzyl-ndodccyl ether methosulfate 80 grams of dlmethyl sulfate are dropped into 64 grams of 4-N,N-dimethylaminobenzyl-ndodecyl ether over a period of 30 minutes and at room temperature (25 CJ. The mixture immediately becomes hot andthe color becomes first green and then yellow. The mixture is heated on the steam bath for one hour and then allowed to cool to room temperature. There is thus formed a water-soluble mass of the consistency of crystalline wax. Two crystallizations from dloxane result in white, soft crystals, melting at 93'-94' C. The yield is 72 grams or 80% of theory.

4-trimethylammonium benzyl-n-dodecyl ether methosulfate, when tested according to the U. S. Food and Drug Administration method (Circular 198, December 1931) kills Eberthella tz/phi and Staphylococcus ,aureus in ten minutes at C. in concentrations of 1:15000 to 1:25000.

Exams 2 Preparation of Z-methul-S-MN-dimethylamino benzyl alcohol A mixture or 200 grams NN-dimethyl-p-toluldine, 200 grams concentrated hydrochloric acid (Sp. G.=1.l9) and 600 grams aqueous iormah dehyde (38%) is kept on the steam bath for 24 hours. The solution is llowed to cool to about 25 C. and is made alkaline by the slow addition oi 700 grams of 20% aqueous sodium hydroxide The isopropyl ether is distilled off and the residue fractionated under a pressure of 5 mm. of mer-' cury. 24 grams, consisting mostly of unchanged dimethyl-p-toluidine are collected up to 90 C.; a mixed fraction (11 grams) is distilled from 90' to 110 0.; and at 110 to 111 C., 109 grams of 2-methyl-5-N,N-dimethylamino benzyl alcohol are obtained.

' menses l Preparation of Z-methbl-t-Nfl-dlmethylamlnobenzvl-n-dodecul-ether 11.5 gramsfoi sodium were cut into small. thin pieces. and added to 115 grams of xylene, dried over sodium. The mixture was well stirred. and heated. At reilux temperature, 132 grams of 2-methyl-5-N.N-dimethyiamlno benzyl alcohol were dropped in during one hour. Refluxing was continued for about another hour until all the sodium had disappeared and the sodium salt of the benzyl alcohol derivative was formed. 102 grams of lauryl chloride were then added and stirring and refluxing continued for two hours. The mixture was then poured into 500 grams of water, the oil layer separated and dried with anhydrous potassium carbonate. After the xylene was driven oil, the residual oil was distilled at a pressure of 4 mm. of mercury and the followin fractions collected:

Boiling Yield,

Fraction mm UP to 140-1 mil-207 Fraction I consists of unchanged 2-methyl-5- N,N-dimethylamino benzyl alcohol and lauryl chloride; and traction 111 represents the desired ether in a yield of 87% of the theory.

This novel ether, 2-methyl-5-N,N -dimethyl.- amlno-benzyl-n-dodecyl ether, is a yellowish, viscous oil, having a boiling point of 205-207 at 4 mm. of mercurypressure.

Preparation of Z-mcthyl-S-trimethvlammmium benzul-n-dodecyl ether methosaljate A mixture of 44.4 grams of 2-methyl-5-N,N-dimethylamino benzyl-n-dodecyl ether, 20 grams of dimethyl sulfate and 34 cc. of benzene are refluxed in an oil bath at-120' C. for 4 hours, under atmospheric pressure. The benzene and excess dimethyl sulfate are then distilled under reduced pressure (100 mm. Hg). The residue (62 grams) was washed with grams of petroleum ether and again freed from remaining solvent by heating in vacuo. After recrystallization from dioxane. the quaternary salt is obtained in the form of white, soft, thin platelets melting at 130.5-132 C. A second crystallization from dioxane yields crystals melting at 132-133 C.

2-methyl 5 trimethylammonlum benzyl-ndodecyl ether methosulfate, when tested according to the U. 8. Food and Drug Administration method Circular 198, December 1931), kills (a). Eberthella tvphi in a concentration of 1:25000 to 1:35000 and (b) Staphylococcus aureus in a concentration oi 1:20000 to 1:30000, when exposed at 20C. for ten minutes.

' Exauru 3 Preparation of z-methyl-4-N,N-dimethylamino benzyl alcohol anhydrous. potassium carbonate. JIhe isopropyl ether was distilled ofland the residue distilled in vacuo (-6 mm. of mercury pressure). The 101- lowing iractions were collected:

Fraction II consisted or the desired 2-rnethyl-4- N.N,-dimethylamino benzyl alcohol.

Preparation of z-methyl-4-N,Ndimethylaminobenzyl-n-dodecyl ether 2.3 grams of sodium were cut into small,- thin pieces and added to 23 grams of xylene, dried over sodium. The mixture was stirred and heated to reflux temperature. 23 grams of 2-methyl- 4-N,N-dimethylamino' benzyl alcohol were then dropped in during one hour. After the sodium had gone into solution, 25 grams of lauryl bromide were added and stirring and refluxing continued for two hours. The mixture was then poured into 300 grams of water, the oilseparated and dried by means of anhydrous potassium carbonate. Xylene was removed by distillation under diminished pressure and theresidue was fractionated at a pressure'oi 5-6 mm. of mercury. 21 grams distilled from 80-210; at 225-230, 11 grams of the 2-methyl-4-N,N-dimethylaminobenzyl-n-dodecyl other were collected.

This ether is a light yellow, viscous liquid which may be used as a solvent, plasticlzer and intermediate for organic compounds.

Preparation of 2-methyl-4-trimethylammonium benzyl dodecyl ether ,methosuljate 6.4 grams of 2-methyl-4-dimethylaminobenzyl dodecyl ether, 3 grams of dimethyl sulfate and 3 c. c. of benzene were heated on the steam bath for 2 hours. The benzene and excess dimethyl sulfate were then removed by heating the viscous oil to about 100 C. and applying diminished pressure, using finally a vacuum of 4 mm. of mercury. The residue was then washed with 30 grams of petroleum ether and again dried in vacuo. 8 grams of a light-tan colored, waxy substance remained which was clearly soluble in water. This is 2-methyl-4-trimethylammonium benzyl dodecyl ether methosulfate.

This material, when tested at 20 C. for ten minutes according to the U, S. Food and Drug Administration method (Circular 198, December, 1931), kills Eberthella typhi in concentrations of 1:15000 to 1:25000. In similar manner, the following quaternary salts were prepared:

. 2-methyl-5-trimethylammonium benzyl-Z-ethyln-hexyl ether methosulfate 2-methyl-5-trimethylammonium benzyl-n-octyl ether methosulfate 2-methyl-5-trimethylammonium benzyl-n-decyl ether methosulfate '2-methyl-5-trimethylammonium benzyl-n-tetradecyl ether methosulfate 2-methyl-4-diethyl-methylammonium benzyl-ndodecyl ether methosuliate 3-chloro-6-trimethylammonium benzyl-n-dodecyl ether methosulfate 3-ch10ro-4-trimethylammonlum benzyl-n-decyl ether methosultate 3-chloro-4-trimethylammonium benzyl-n-dodecyl ether methosulfate 3-chloro-4-trimethylammonium benzyl-n-hexadecyl ether methosuliate 3-bromo-6-trimethylammonium benzylndodecyl ether methosulfate The foregoing quaternary ammonium compounds, as first isolated, are viscous oils or waxes, of yellowish or brownish color. After crystallization attempts, using a suitable solvent, as, for example, dioxane, some of'the compounds retain their oily or waxy characteristics, whereas others form crystalline solids. All, however, are quite soluble in water whether in the form as first isolated or after crystallization attempts as just noted; and all likewise possess desirable bactericidal properties. The foregoing illustrates the practice of my invention which, however, is not to be limited thereby but is to be construed and limited solely by the appended claims.

I claim:

1. New quaternary ammonium compounds hav. 7

ing the general formula:

R1 m-o-cm-Ar N-n, An R:

wherein R4 is an alkyl radical having 8 to 18 carbon atoms.

3. As a new compound, -trimethylammonium benzyl-n-dodecyl ether methosulfate.

4. As a new compound, 2-methyl-5-trimethylammonium benzyl-n-dodecyl ether methosuliate.

5. As a new compound 2-methyl-4-trimethylammonium benzyl-n-dodecyl ether methosuliate.

WILLIAM S. GUMIP.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Number Name Date 2,216,446 McNally Oct. 1, 1940 2,273,564 Dickey Feb. 17, 1942 OTHER REFERENCES Chemical Abstracts, vol. 22 (1928), pp, 1970-71; vol. 8 (1914) p. 93.

Beilstein, Handbuch der Organische Chemie, supp. to vol. XIII, p. 231. 

